Topical and transdermal administration of peptidyl drugs using hydroxide releasing agents as permeation enhancers

ABSTRACT

A method is provided for increasing the permeability of skin or mucosal tissue to a topically or transdermally administered pharmacologically or cosmeceutically active peptide, polypeptide or protein. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the peptide, polypeptide or protein through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery devices employing hydroxide-releasing agents as permeation enhancers are provided as well.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. Ser. No. 09/687,937, filed Oct.13, 2000 which is a continuation-in-part of U.S. Ser. No. 09/569,889,filed May 11, 2000 which is a continuation-in part of U.S. Ser. No.09/465,098, filed Dec. 16, 1999, the disclosures of which areincorporated by reference.

TECHNICAL FIELD

This invention relates generally to topical and transdermaladministration of pharmacologically active peptidyl drugs, and moreparticularly relates to methods and compositions for administeringpeptidyl drugs transdermally.

BACKGROUND

The delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences—e.g., gastrointestinal irritation, degradationof certain drugs via gastrointestinal enzymes and the like—areeliminated as well. Transdermal drug delivery also makes possible a highdegree of control over blood concentrations of any particular drug.

Skin is a structurally complex, relatively thick membrane. Moleculesmoving from the environment into and through intact skin must firstpenetrate the stratum corneum and any material on its surface. They mustthen penetrate the viable epidermis, the papillary dermis, and thecapillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the cells of the stratum corneumwhich present the primary barrier to absorption of topical compositionsor transdermally administered drugs. The stratum corneum is a thin layerof dense, highly keratinized cells approximately 10-15 microns thickover most of the body. It is believed to be the high degree ofkeratinization within these cells as well as their dense packing whichcreates in most cases a substantially impermeable barrier to drugpenetration. With many drugs, the rate of permeation through the skin isextremely low and is particularly problematic for high molecular weightdrugs such as peptides, polypeptides and proteins. Consequently, a meansfor enhancing the permeability of the skin is desired to effecttransport of the drug into and through intact skin.

U.S. Pat. No. 6,004,566 to Friedman et al. describes compositions ofsubmicron drops containing a peptide with oil excipients for topicalapplication. The manufacture of submicron preparations, however,requires many steps and can be expensive.

In order to increase the rate at which a drug penetrates through theskin, then, various approaches have been followed, each of whichinvolves the use of either a chemical penetration enhancer or a physicalpenetration enhancer. Physical enhancement of skin permeation includes,for example, electrophoretic techniques such as iontophoresis. The useof ultrasound (or “phonophoresis”) as a physical penetration enhancerhas also been researched. Chemical enhancers are compounds that areadministered along with the drug (or in some cases the skin may bepretreated with a chemical enhancer) in order to increase thepermeability of the stratum corneum, and thereby provide for enhancedpenetration of the drug through the skin. Ideally, such chemicalpenetration enhancers (or “permeation enhancers,” as the compounds arereferred to herein) are innocuous compounds that serve merely tofacilitate diffusion of the drug through the stratum corneum.

Various compounds for enhancing the permeability of skin are known inthe art and described in the pertinent texts and literature. Compoundsthat have been used to enhance skin permeability include: sulfoxidessuch as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C₁₀MSO);ethers such as diethylene glycol monoethyl ether (available commerciallyas Transcutol®) and diethylene glycol monomethyl ether; surfactants suchas sodium laurate, sodium lauryl sulfate, cetyltrimethylammoniumbromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20,40, 60, 80) and lecithin (U.S. Pat. No. 4,783,450); the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one(available under the trademark Azone® from Nelson Research & DevelopmentCo., Irvine, Calif.; see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616and 4,557,934); alcohols such as ethanol, propanol, octanol, benzylalcohol, and the like; fatty acids such as lauric acid, oleic acid andvaleric acid; fatty acid esters such as isopropyl myristate, isopropylpalmitate, methylpropionate, and ethyl oleate; polyols and estersthereof such as propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see,e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compoundssuch as urea, dimethylacetamide (DMA), dimethylformamide (DMF),2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; organic acids, particularlysalicylic acid and salicylates, citric acid and succinic acid; andcertain peptides, e.g., peptides having Pro-Leu at the N-terminus andfollowed by a protective group (see U.S. Pat. No. 5,534,496).Percutaneous Penetration Enhancers, eds. Smith et al. (CRC Press, 1995)provides an excellent overview of the field and further backgroundinformation on a number of chemical and physical enhancers.

With regard to peptidyl drugs, U.S. Pat. No. 5,863,555 to Heiber et al.describes transbuccal delivery systems of a glucagon-like insulinotropicpeptide. The described delivery systems include, inter alia, many of theabove-mentioned permeation enhancers such as surfactants and fattyacids. U.S. Pat. No. 5,449,670 to Skinner et al. describes transdermaldelivery of a biologically active peptide. Effective delivery of thebiologically active peptide, however, requires the presence of apyrrolidone compound.

Although many chemical permeation enhancers are known, there is anongoing need for an enhancer that (1) is highly effective in increasingthe rate at which a pharmacologically active agent permeates the skin,and (2) does not result in skin damage, irritation, sensitization, orthe like. In particular, there is a need for a chemical permeationenhancer that enables the transdermal administration of high molecularweight drugs such as peptidyl drugs. It has now been discovered thathydroxide-releasing agents are highly effective permeation enhancers,even when used without co-enhancers, and provide all of theaforementioned advantages relative to known permeation enhancers.Furthermore, in contrast to conventional enhancers, transdermaladministration of drugs with hydroxide-releasing agents as permeationenhancers, employed at the appropriate levels, does not result insystemic toxicity.

SUMMARY OF THE INVENTION

It is thus a primary object of the invention to address theabove-described need in the art by providing a method for transdermallyadministering a pharmacologically active peptide, polypeptide orprotein.

It is another object of the invention to provide such a method wherein ahydroxide-releasing agent is employed as a permeation enhancer toincrease the flux of a pharmacologically active peptide, polypeptide orprotein through a patient's skin or mucosal tissue.

It is still another object of the invention to provide such a methodwherein the amount of hydroxide-releasing agent employed is optimized toenhance permeation while minimizing or eliminating the possibility ofskin damage, irritation or sensitization.

It is a further object of the invention to provide such a method whereinthe active agent is a cosmeceutically effective agent.

It is an additional object of the invention to provide formulations anddrug delivery systems for carrying out the aforementioned methods.

Additional objects, advantages and novel features of the invention willbe set forth in part in the description that follows, and in part willbecome apparent to those skilled in the art upon examination of thefollowing, or may be learned by practice of the invention.

In one aspect of the invention, then, a method is provided forincreasing the rate at which a peptidyl drug permeates through the bodysurface of a patient. The method involves administering the peptidyldrug to a predetermined area of the patient's body surface incombination with a hydroxide-releasing agent in a predetermined amounteffective to enhance the flux of the peptidyl drug through the bodysurface without causing damage thereto. The predetermined amount of thehydroxide-releasing enhancer is preferably an amount effective toprovide a pH at the body surface in the range of about 8.0 to 13,preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5, duringdrug administration. If a skin patch is used, this is the preferred pHat the interface between the basal surface of the patch (i.e., theskin-contacting or mucosal-contacting surface of the patch) and the bodysurface. The optimal amount (or concentration) of any onehydroxide-releasing agent will, however, depend on the specifichydroxide-releasing agent, i.e., on the strength or weakness of thebase, its molecular weight, and other factors as will be appreciated bythose of ordinary skill in the art of transdermal drug delivery. Thisoptimal amount may be determined using routine experimentation to ensurethat the pH at the body surface is within the aforementioned ranges,i.e., in the range of about 8.0 to 13, preferably about 8.0 to 11.5,more preferably about 8.5 to 11.5. A conventional transdermal drugdelivery device or “patch” may be used to administer the active agent,in which case the drug and hydroxide-releasing agent are generallypresent in a drug reservoir or reservoirs. However, the drug andhydroxide-releasing agent may also be administered to the body surfaceusing a liquid or semisolid formulation. Alternatively, or in addition,the body surface may be pretreated with the enhancer, e.g., treated witha dilute solution of the hydroxide-releasing agent prior to transdermaldrug administration. Such a solution will generally be comprised of aprotic solvent (e.g., water or alcohol) and have a pH in the range ofabout 8.0 to 13, preferably about 8.0 to 11.5, more preferably 8.5 to11.5.

In a related aspect of the invention, a composition of matter isprovided for delivering a drug through a body surface using ahydroxide-releasing agent as a permeation enhancer. Generally, theformulation comprises (a) a therapeutically effective amount of a drug,(b) a hydroxide-releasing agent in an amount effective to enhance theflux of the drug through the body surface without causing damagethereto, and (c) a pharmaceutically acceptable carrier suitable fortopical or transdermal drug administration. The composition may be inany form suitable for application to the body surface, and may comprise,for example, a cream, lotion, solution, gel, ointment, paste or thelike, and/or may be prepared so as to contain liposomes, micelles,and/or microspheres. The composition may be directly applied to the bodysurface or may involve use of a drug delivery device. In either case, itis preferred although not essential that water be present in order forthe hydroxide-releasing agent to generate hydroxide ions and thusenhance the flux of the active agent through the patient's body surface.Thus, a formulation or drug reservoir may be aqueous, i.e., containwater, or may be nonaqueous and used in combination with an occlusiveoverlayer so that moisture evaporating from the body surface ismaintained within the formulation or transdermal system during drugadministration. In some cases, however, e.g., with an occlusive gel, anonaqueous formulation may be used with or without an occlusiveoverlayer.

In another aspect of the invention, a drug delivery system is providedfor the topical or transdermal administration of a drug using ahydroxide-releasing agent as a permeation enhancer. The system willgenerally comprise: at least one drug reservoir containing the drug andthe hydroxide-releasing agent in an amount effective to enhance the fluxof the drug through the body surface without causing damage thereto; ameans for maintaining the system in drug and enhancer transmittingrelationship to the body surface; and a backing layer that serves as theouter surface of the device during use. The backing layer may beocclusive or nonocclusive, although it is preferably occlusive. The drugreservoir may be comprised of a polymeric adhesive, which may serve asthe basal surface of the system during use and thus function as themeans for maintaining the system in drug and enhancer transmittingrelationship to the body surface. The drug reservoir may also becomprised of a hydrogel, or it may be a sealed pouch within a“patch”-type structure wherein the drug and hydroxide-releasing agentare present in the pouch as a liquid or semi-solid formulation.

The peptidyl drug incorporated as part of the invention may be anypeptidyl drug that provides a desired pharmacological effect. Generalcategories of such peptidyl drugs include, for example, coagulationmodulators, cytokines, endorphins, hormones, analogs of LHRH(luteinizing hormone-releasing hormone) and kinins.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and Overview:

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific drug deliverysystems, device structures, enhancers or carriers, as such may vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “peptidyl drug” includes a mixture of two or more suchdrugs, reference to “a hydroxide-releasing agent” includes mixtures oftwo or more hydroxide-releasing agents, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

Amino acid residues in peptides described herein are abbreviated asfollows: glutamine is Gln or Q; leucine is Leu or L; methionine is Metor M; and proline is Pro or P.

Stereoisomers (e.g., D-amino acids) of conventional amino acids,unnatural amino acids such as α,α-disubstituted amino acids, N-alkylamino acids, lactic acid, and other unconventional amino acids may alsobe present in the peptidyl drugs that can be administered using themethod. Examples of unconventional amino acids include, withoutlimitation, β-alanine, 1-naphthylalanine, 2-naphthylalanine,3-pyridylalanine, 4-hydroxyproline, O-phosphoserine, N-acetylserine,N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, nor-leucine, andother similar amino acids and imino acids (e.g., 4-hydroxyproline).

The terms “active agent,” “drug” and “pharmacologically active agent”are used interchangeably herein to refer to a compound or composition ofmatter which, when administered to an organism (human or animal),induces a desired pharmacologic, physiologic and/or cosmeceutical effectby local or systemic action. The active agents herein are peptidyl drugsand derivatives and analogs of those compounds or classes of compoundsspecifically mentioned which also induce the desired effect.

A “peptidyl drug” as used herein is an active agent, drug orpharmacologically active agent that comprises a peptide, polypeptide orprotein. Pharmacologically active derivatives and fragments of peptidyldrugs are included as well. For ease of discussion, a “peptidyl drug”will also include a single amino acid and derivatives thereof.

A “peptide” refers to a polymer in which the monomers are amino acidslinked together through amide bonds. “Peptides” are generally smallerthan proteins, i.e., about two to about ten amino acids in length. Theterm “peptide” includes “dipeptides” comprised of two amino acids and“tripeptides” comprised of three consecutively linked amino acids, andso forth.

A “polypeptide” refers to a polymer of amino acids generally comprisedof about ten to about fifty amino acids.

A “protein” as used herein refers to a polymer of amino acidsconventionally comprised of over fifty amino acids. The proteins thatmay be used as peptidyl drugs in the present invention may be naturallyoccurring proteins, modified naturally occurring proteins, or chemicallysynthesized proteins that may or may not be identical to naturallyoccurring proteins.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. The presentmethod of “treating” a patient or individual, as the term is usedherein, thus encompasses both prevention of a disorder in a predisposedindividual and treatment of the disorder in a clinically symptomaticindividual.

The term “hydroxide-releasing agent” as used herein is intended to meanan agent that releases free hydroxide ions in an aqueous environment.The agent may contain hydroxide ions and thus release the ions directly(e.g., an alkali metal hydroxide), or the agent may be one that is actedupon chemically in an aqueous environment to generate hydroxide ions(e.g., a metal carbonate).

By “therapeutically effective” amount is meant a nontoxic but sufficientamount of an active agent to provide the desired therapeutic effect.

By “transdermal” drug delivery is meant administration of a drug to theskin surface of an individual so that the drug passes through the skintissue and into the individual's blood stream, thereby providing asystemic effect. The term “transdermal” is intended to include“transmucosal” drug administration, i.e., administration of a drug tothe mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of anindividual so that the drug passes through the mucosal tissue and intothe individual's blood stream.

The term “topical administration” is used in its conventional sense tomean delivery of a topical drug or pharmacologically active agent to theskin or mucosal, as in, for example, the treatment of various skindisorders. Topical administration, in contrast to transdermaladministration, provides a local rather than a systemic effect. Unlessotherwise stated or implied, the terms “topical drug administration” and“transdermal drug administration” are used interchangeably.

The term “body surface” is used to refer to skin or mucosal tissue.

By “predetermined area” of skin or mucosal tissue, which refers to thearea of skin or mucosal tissue through which a drug-enhancer formulationis delivered, is intended a defined area of intact unbroken living skinor mucosal tissue. That area will usually be in the range of about 5 cm²to about 200 cm², more usually in the range of about 5 cm² to about 100cm², preferably in the range of about 20 cm² to about 60 cm². However,it will be appreciated by those skilled in the art of drug delivery thatthe area of skin or mucosal tissue through which drug is administeredmay vary significantly, depending on patch configuration, dose, and thelike.

“Penetration enhancement” or “permeation enhancement” as used hereinrelates to an increase in the permeability of the skin or mucosal tissueto the selected pharmacologically active agent, i.e., so that the rateat which the agent permeates therethrough (i.e., the “flux” of the agentthrough the body surface) is increased relative to the rate that wouldbe obtained in the absence of permeation enhancement. The enhancedpermeation effected through the use of such enhancers can be observed bymeasuring the rate of diffusion of drug through animal or human skinusing, for example a Franz diffusion apparatus as known in the art andas employed in the Examples herein.

An “effective” amount of a permeation enhancer is meant a nontoxic,nondamaging but sufficient amount of the enhancer to provide the desiredincrease in skin permeability and, correspondingly, the desired depth ofpenetration, rate of administration, and amount of drug delivered.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration. Carriers and vehiclesuseful herein include any such materials known in the art which arenontoxic and do not interact with other components of the composition ina deleterious manner.

The term “aqueous” refers to a formulation or drug delivery system thatcontains water or that becomes water-containing following application tothe skin or mucosal tissue.

In one embodiment, then, the invention pertains to a method, compositionand drug delivery system for treating an individual with a peptidyldrug-responsive condition or disease. The invention increases the rateat which the peptidyl drug permeates through the body surface of apatient wherein the method involves administering the peptidyl drug to apredetermined area of the patient's body surface in combination with ahydroxide-releasing agent in an amount effective to enhance the flux ofthe agent through the body surface without causing damage thereto.

The Hydroxide-Releasing Agent:

The “hydroxide-releasing agent” is a chemical compound that releasesfree hydroxide ions in the presence of an aqueous fluid. The aqueousfluid may be natural moisture at the skin surface, or a patch orcomposition that is used may contain added water, and/or be used inconnection with an occlusive backing. Similarly, any liquid or semisolidformulation that is used should be aqueous or used in conjunction withan overlayer of an occlusive material.

Any hydroxide-releasing agent may be used provided that the compoundreleases free hydroxide ions in the presence of an aqueous fluid.Examples of suitable hydroxide-releasing agents include, but are notlimited to, inorganic hydroxides, inorganic oxides, and alkali metal oralkaline earth metal salts of weak acids. Inorganic hydroxides include,for example, ammonium hydroxide, alkali metal hydroxide and alkalineearth metal hydroxides, such as sodium hydroxide, calcium hydroxide,potassium hydroxide, magnesium hydroxide, and the like. Inorganic oxidesinclude, for example, magnesium oxide, calcium oxide, and the like.Metal salts of weak acids include, for example, sodium acetate, sodiumborate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodiumphosphate (tribasic), sodium phosphate (dibasic), potassium carbonate,potassium bicarbonate, potassium citrate, potassium acetate, potassiumphosphate (dibasic), potassium phosphate (tribasic), ammonium phosphate(dibasic), and the like. Preferred hydroxide-releasing agents are metalhydroxides such as sodium hydroxide and potassium hydroxide.

It is important that the amount of hydroxide-releasing agent in anypatch or formulation is optimized so as to increase the flux of thepeptidyl drug through the body surface while minimizing any possibilityof skin damage. In general, this means that the pH at the body surfacein contact with a formulation or drug delivery system of the invention(i.e., the interface between the body surface and the formulation ordelivery system) should be in the range of approximately 8.0 to 13,preferably about 8.0 to 11.5, more preferably about 8.5 to 11.5. Thiswill typically although not necessarily mean that the pH of theformulation or the drug composition contained within a delivery systemwill be in the range of approximately 8.0 to 13, preferably about 8.0 to11.5, more preferably about 8.5 to 11.5.

For inorganic hydroxides, the amount of hydroxide-releasing agent willtypically represent about 0.25 wt. % to 7.0 wt. %, preferably about 0.5wt. % to 4.0 wt. %, more preferably about 0.75 wt. % to 2.0 wt. % andoptimally about 1.0 wt. %, of a topically applied formulation or of adrug reservoir of a drug delivery system or “patch.” That is, forpeptidyl drugs that react, e.g., undergo hydrolysis, with the inorganichydroxide, the inorganic hydroxide should be present in an amount justsufficient to neutralize the drug, plus an additional amount (i.e.,about 0.25 wt. % to 7.0 wt. %, preferably about 0.5 wt. % to 4.0 wt. %,more preferably about 0.75 wt. % to 2.0 wt. % and optimally about 1.0wt. %) to enhance the flux of the drug through the skin or mucosaltissue. For patches, the aforementioned percentages are given relativeto the total dry weight of the formulation components and the adhesive,gel or liquid reservoir.

For other hydroxide-releasing agents such as inorganic oxides and metalsalts of weak acids, the amount of hydroxide-releasing agent in theformulation or drug delivery system may be substantially higher, as highas about 20 wt. %, in some cases as high as about 25 wt. % or higher,but will generally be in the range of about 2 wt. % to about 20 wt. %.

Still greater amounts of hydroxide-releasing agent may be used bycontrolling the rate and/or quantity of release of thehydroxide-releasing agent preferably during the drug delivery perioditself.

However, for all hydroxide-releasing agents herein, the optimum amountof any particular agent will depend on the strength or weakness of thebase, the molecular weight of the base, and other factors such as thenumber of ionizable sites in the drug administered and any other acidicspecies in the formulation or patch. One skilled in the art may readilydetermine the optimum amount for any particular agent by ensuring that aformulation or drug delivery system should in all cases be effective toprovide a pH at the skin surface in the range of about 8.0 to 13,preferably in the range of about 8.0 to 11.5, more preferably in therange of about 8.5 to 11.5, during application to reach the desired pHat the body surface. This in turn ensures that the degree of enhancementis optimized while the possibility of damage to the body surface iseliminated or at least substantially minimized.

The Peptidyl Drug:

The peptidyl drug is any pharmacologically active peptide, polypeptideor protein. Once chosen, the peptidyl drug must be prepared or obtainedfrom commercial suppliers for incorporation in a composition or deliverysystem. The peptidyl drug may be prepared using standard synthetictechniques, recombinant technology or extraction from natural sources.

Synthetic production of peptides, polypeptides and proteins generallyemploys techniques of standard solid phase peptide synthesis well knownin the art. In such a method, the synthesis is sequentially carried outby incorporating the desired amino acid residues one at a time onto agrowing peptide chain according to the general principles of solid phasesynthesis as described, for example, by Merrifield (1963) J. Amer. Chem.Soc. 85:2149-2154. Common to chemical syntheses of peptides,polypeptides and proteins is the protection of reactive side chaingroups of the various amino acid moieties with suitable protectinggroups which will prevent a chemical reaction from occurring at thatsite until the protecting group is ultimately removed. It is also wellknown to protect the α-amino group on an amino acid while that entityreacts at the carboxyl group, followed by the selective removal of theα-amino protecting group to allow a subsequent reaction to take place atthat site. Examples of suitable α-amino and side chain protecting groupsare well known in the art.

Alternatively, the peptide, polypeptide or protein may be prepared byemploying recombinant technology via techniques well known in the art.That is, conventional recombinant techniques may be used, which, as willbe appreciated by those skilled in the art, involves constructing DNAencoding the desired amino acid sequence, cloning the DNA into anexpression vector, transforming a host cell, e.g., a bacterial, yeast,or mammalian cell, and expressing the DNA to produce the desiredpeptide, polypeptide or protein.

Additionally, peptides, polypeptides or proteins can be obtained fromnatural sources such as a human or other animal, and may be extractedfrom either a living organism or from a cadaver. The material isseparated and purified prior to incorporation into a drug deliverysystem or dosage form. Techniques of separation and purification arewell known in the art and include, for example, centrifugation andchromatography.

The peptidyl drug administered may be any compound that is suitable fortopical or transdermal delivery and induces a desired local or systemiceffect. Such substances include the broad classes of compounds normallydelivered through body surfaces and membranes, including skin. Ingeneral, this includes: analgesic agents; anesthetic agents;antiarthritic agents; respiratory drugs, including antiasthmatic agents;anticancer agents, including antineoplastic drugs; anticholinergics;anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals;antihelminthics; antihistamines; antihyperlipidemic agents;antihypertensive agents; anti-infective agents such as antibiotics andantiviral agents; antiinflammatory agents; antimigraine preparations;antinauseants; antineoplastic agents; antiparkinsonism drugs;antipruritics; antipsychotics; antipyretics; antispasmodics;antitubercular agents; antiulcer agents; antiviral agents; anxiolytics;appetite suppressants; attention deficit disorder (ADD) and attentiondeficit hyperactivity disorder (ADHD) drugs; cardiovascular preparationsincluding calcium channel blockers, CNS agents; antiarrhythmic agents;central nervous system stimulants; cough and cold preparations,including decongestants; diuretics; genetic materials; hormonolytics;hypnotics; hypoglycemic agents; immunosuppressive agents; leukotrieneinhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists;nutritional agents such as essential amino acids; ophthalmic drugs suchas antiglaucoma agents; parasympatholytics; psychostimulants; sedatives;sympathomimetics; tranquilizers; and vasodilators including generalcoronary, peripheral and cerebral.

Although any peptidyl drug may be incorporated into the delivery systemsof the present invention, the drug is generally selected fromcoagulation modulators, cytokines, endorphins, hormones, LHRH(luteinizing hormone-releasing hormone) analogs, kinins, and otherpeptidyl drugs that provide a desired pharmacological activity. Ofcourse, the categories provided are not intended to be limiting andsimply serve as a means for organization. As will be appreciated, apeptidyl drug may fall into more than one category.

Coagulation modulators: Many coagulation modulators are endogenousproteins that circulate in the blood and interact with other endogenousproteins to control blood coagulation. Preferred coagulation modulatorsinclude α₁-antitrypsin, α₂-macroglobulin, antithrombin III, factor I(fibrinogen), factor II (prothrombin), factor III (tissue prothrombin),factor V (proaccelerin), factor VII (proconvertin), factor VIII(antihemophilic globulin or AHG), factor IX (Christmas factor, plasmathromboplastin component or PTC), factor X (Stuart-Power factor), factorXI (plasma thromboplastin antecedent or PTA), factor XII (Hagemanfactor), heparin cofactor II, kallikrein, plasmin, plasminogen,prekallikrein, protein C, protein S, thrombomodulin and combinationsthereof. When applicable, both the “active” and “inactive” versions ofthese proteins are included.

Cytokines: The cytokines are a large and heterogeneous group ofimmunoregulatory proteins that have a role in the function of the immunesystem and the control of hematopoiesis, i.e., the production of bloodor blood cells. Preferred cytokines include colony stimulating factor 4,heparin binding neurotrophic factor (HBNF), interferon-α, interferonα-2a, interferon α-2b, interferon α-n3, interferon-β, interferon-γ,interleukin-1, interleukin-2, interleukin-3, interleukin-4,interleukin-5, interleukin-6, interleukin-7, interleukin-8,interleukin-9, interleukin-10, interleukin-11, interleukin-12,interleukin-13, interleukin-14, interleukin-15, interleukin-16,interleukin-17, tumor necrosis factor, tumor necrosis factor-α,granuloycte colony-stimulating factor (G-CSF), granulocyte-macrophagecolony-stimulating factor (GM-CSF), macrophage colony-stimulatingfactor, midkine (MD), thymopoietin and combinations thereof.

Endorphins: Endorphins are generally peptides or small-chain peptidesthat activate opiate receptors. Agonist and antagonist derivatives ofthe naturally-occurring endophins are also contemplated. Representativeexamples of endorphins or pharmacologically active derivatives includedermorphin, dynorphin, α-endorphin, β-endorphin, γ-endorphin,σ-endorphin [Leu⁵]enkephalin, [Met⁵]enkephalin, substance P, andcombinations thereof

Hormones: Many hormones are derived from peptides. A peptidyl hormonethat may administered according to the invention may be naturallyoccurring or may be a pharmacologically active derivative of a knownhormones. In addition, the peptidyl hormones may be human or be derivedfrom other animal sources. Examples of peptidyl hormones forincorporation in the present invention include activin, amylin,angiotensin, atrial natriuretic peptide (ANP), calcitonin (derived fromchicken, eel, human, pig, rat, salmon, etc.), calcitonin gene-relatedpeptide, calcitonin N-terminal flanking peptide, cholecystokinin (CCK),ciliary neurotrophic factor (CNTF), corticotropin (adrenocorticotropinhormone, ACTH), corticotropin-releasing factor (CRF or CRH), epidermalgrowth factor (EGF), follicle-stimulating hormone (FSH), gastrin,gastrin inhibitory peptide (GIP), gastrin-releasing peptide, ghrelin,glucogon, gonadotropin-releasing factor (GnRF or GNRH), growth hormonereleasing factor (GRF, GRH), human chorionic gonadotropin (hCH), inhibinA, inhibin B, insulin (derived from beef, human, pig, etc.), leptin,lipotropin (LPH), luteinizing hormone (LH), luteinizinghormone-releasing hormone (LHRH), α-melanocyte-stimulating hormone,β-melanocyte-stimulating hormone, γ-melanocyte-stimulating hormone,melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide,parathyroid hormone (PTH), placental lactogen, prolactin (PRL),prolactin-release inhibiting factor (PIF), prolactin-releasing factor(PRF), secretin, somatotropin (growth hormone, GH), somatostatin (SIF,growth hormone-release inhibiting factor, GIF), thyrotropin(thyroid-stimulating hormone, TSH), thyrotropin-releasing factor (TRH orTRF), thyroxine, triiodothyronine, vasoactive intestinal peptide (VIP),vasopressin (antidiuretic hormone, ADH) and combinations thereof.

LHRH analogs: Particularly preferred analogs of LHRH include buserelin,deslorelin, fertirelin, goserelin, histrelin, leuprolide (leuprorelin),lutrelin, nafarelin, tryptorelin and combinations thereof.

Kinins: Particularly preferred kinins include bradykinin, potentiator B,bradykinin potentiator C, kallidin and combinations thereof.

Other peptidyl drugs: Still other peptidyl drugs that provide a desiredpharmacological activity can be incorporated into the compositions anddelivery systems of the invention. Examples include abarelix, adenosinedeaminase, anakinra, ancestim, alteplase, alglucerase, asparaginase,bivalirudin, bleomycin, bombesin, desmopressin acetate, des-Q14-ghrelin,domase-α, enterostatin, erythropoeitin, exendin-4, fibroblast growthfactor-2, filgrastim, β-glucocerebrosidase, gonadorelin, hyaluronidase,insulinotropin, lepirudin, magainin I, magainin II, nerve growth factor,pentigetide, thrombopoietin, thymosin α-1, thymidin kinase (TK), tissueplasminogen activator, tryptophan hydroxylase, urokinase, urotensin IIand combinations thereof.

Particularly preferred systemically active agents that can beadministered transdermally in conjunction with the present inventioninclude oxytocin, insulin and LHRH analogs, such as leuprolide.

Preferred agents for local, topical administration are within the broadclasses of compounds known to be topically administrable, including, butnot limited to, topical antibiotics (e.g., magainin I and magainin II),anti-fungal agents, anti-psoriatic agents, antipruritic agents,antihistamines, antineoplastic agents (e.g., asparaginase andbleomycin), local anesthetics, anti-inflammatory agents and the like.

The peptidyl drug may be administered, if desired, in the form of asalt, ester, amide, prodrug, derivative, or the like, provided the salt,ester, amide, prodrug or derivative is suitable pharmacologically.Salts, esters, amides, prodrugs and other derivatives of the activeagents may be prepared using standard procedures known to those skilledin the art of synthetic organic chemistry and described, for example, byJ. March, Advanced Organic Chemistry: Reactions, Mechanisms andStructure, 4th Ed. (New York: Wiley-Interscience, 1992). Suitable acidsfor preparing acid addition salts include both organic acids, e.g.,acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like, as well as inorganic acids, e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. An acid addition salt may be reconvertedto the free base by treatment with a suitable base. Conversely, basicsalts of acid moieties are prepared using a pharmaceutically acceptablebase such as sodium hydroxide, potassium hydroxide, ammonium hydroxide,calcium hydroxide, trimethylamine, or the like. Preparation of estersinvolves functionalization of hydroxyl and/or carboxyl groups presentwithin the molecular structure of the drug. The esters are typicallyacyl-substituted derivatives of free alcohol groups, i.e., moietieswhich are derived from carboxylic acids of the formula RCOOH where R isalkyl, and preferably is lower alkyl. Amides and prodrugs may also beprepared using techniques known to those skilled in the art or describedin the pertinent literature. Prodrugs are typically prepared by covalentattachment of a moiety which results in a compound that istherapeutically inactive until modified by an individual's metabolicsystem.

One can also replace the naturally occurring side chains of the 20genetically encoded amino acids (or the stereoisomeric D amino acids)with other side chains, for instance with groups such as alkyl, loweralkyl, cyclic 4-, 5-, 6- or 7-membered alkyl, amide, amide lower alkyl,amide di(lower alkyl), lower alkoxy, hydroxy, carboxy and the lowerester derivatives thereof, and 4-, 5-, 6- or 7-membered heterocyclic. Inparticular, proline analogs in which the ring size of the prolineresidue is changed from 5 members to 4, 6, or 7 members can be employed.

One can also readily modify the peptidyl drug by phosphorylation orother methods as described in Hruby et al. (1990) Biochem J.268:249-262. For example, peptide backbones may be replaced with abackbone composed of phosphonates, amidates, carbamates, sulfonamides,secondary amines, and N-methylamino acids.

The active agent administered also may be one that is cosmetically or“cosmeceutically” effective rather than pharmacologically active. Suchagents include, for example, compounds that can reduce the appearance ofaging or photodamaged skin, e.g., and/or cosmetically acceptable salts,esters, amides, or other derivatives thereof.

Formulations:

The method of delivery of the peptidyl drug may vary, but necessarilyinvolves application of a hydroxide-releasing agent either prior to,e.g., when pretreating the body surface, or simultaneously withapplication of the peptidyl drug. Both the hydroxide-releasing agent andthe peptidyl drug are applied (either together or separately) to apredetermined area of the skin or other tissue for a period of timesufficient to provide the desired local or systemic effect. The methodmay involve direct application of a composition containing thehydroxide-releasing agent and/or peptidyl drug as an ointment, gel,cream, or the like, or may involve use of a drug delivery device. Ineither case, water must be present in order for the hydroxide-releasingagent to generate hydroxide ions and thus enhance the flux of the activeagent through the patient's body surface. Thus, a formulation or drugreservoir may be aqueous, i.e., contain water, or may be nonaqueous andused in combination with an occlusive overlayer so that moistureevaporating from the body surface is maintained within the formulationor transdermal system during administration of the hydroxide-releasingagent, and optimally, during administration of the peptidyl drug. Insome cases, e.g., with an occlusive gel, a nonaqueous formulation may beused with or without an occlusive overlayer. Consequently, thehydroxide-releasing agent and the peptidyl drug (either together orseparately) may be incorporated into a suitable formulation and appliedto the skin surface or incorporated into a drug delivery system, e.g., a“patch.”

Suitable formulations include ointments, creams, gels, lotions, pastes,and the like. Ointments, as is well known in the art of pharmaceuticalformulation, are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery, and, preferably, will providefor other desired characteristics as well, e.g., emolliency or the like.As with other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack PublishingCo., 1995), at pages 1399-1404, ointment bases may be grouped in fourclasses: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, see Remington: The Scienceand Practice of Pharmacy for further information.

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferred“organic macromolecules,” i.e., gelling agents, are crosslinked acrylicacid polymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methyl cellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof.

Lotions, which are preferred for delivery of cosmetic agents, arepreparations to be applied to the skin surface without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable base. Depending on the nature of the base, pastes aredivided between fatty pastes or those made from a single-phase aqueousgels. The base in a fatty paste is generally petrolatum or hydrophilicpetrolatum or the like. The pastes made from single-phase aqueous gelsgenerally incorporate carboxymethylcellulose or the like as a base.

Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged) and neutralpreparations. Cationic liposomes are readily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol(DOPG), dioleoylphoshatidyl ethanolamine (DOPE), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

Micelles are known in the art as comprised of surfactant moleculesarranged so that their polar headgroups form an outer spherical shell,while the hydrophobic, hydrocarbon chains are oriented towards thecenter of the sphere, forming a core. Micelles form in an aqueoussolution containing surfactant at a high enough concentration so thatmicelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyl8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol30. Micelle formulations can be used in conjunction with the presentinvention either by incorporation into the reservoir of a topical ortransdermal delivery system, or into a formulation to be applied to thebody surface.

Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. They are generally although not necessarily formed fromlipids, preferably charged lipids such as phospholipids. Preparation oflipidic microspheres is well known in the art and described in thepertinent texts and literature.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solvents, including relativelysmall amounts of alcohol, may be used to solubilize certain drugsubstances. Other optional additives include opacifiers, antioxidants,fragrance, colorant, gelling agents, thickening agents, stabilizers,surfactants and the like. Other agents may also be added, such asantimicrobial agents, to prevent spoilage upon storage, i.e., to inhibitgrowth of microbes such as yeasts and molds. Suitable antimicrobialagents are typically selected from the group consisting of the methyland propyl esters of p-hydroxybenzoic acid (i.e., methyl and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinationsthereof.

For those drugs having an unusually low rate of permeation through theskin or mucosal tissue, it may be desirable to include a secondpermeation enhancer in the formulation in addition to thehydroxide-releasing agent, although in a preferred embodiment thehydroxide-releasing agent is administered without any other permeationenhancers. Any other enhancers should, like the hydroxide-releasingagent itself, minimize the possibility of skin damage, irritation, andsystemic toxicity. Examples of suitable secondary enhancers (or“co-enhancers”) include, but are not limited to: ethers such asdiethylene glycol monoethyl ether (available commercially as Transcutol)and diethylene glycol monomethyl ether; surfactants such as sodiumlaurate, sodium lauryl sulfate, cetyltrimethylammonium bromide,benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80)and lecithin (U.S. Pat. No. 4,783,450; alcohols such as ethanol,propanol, octanol, benzyl alcohol, and the like; fatty acids such aslauric acid, oleic acid and valeric acid; fatty acid esters such asisopropyl myristate, isopropyl palmitate, methylpropionate, and ethyloleate; polyols and esters thereof such as polyethylene glycol, andpolyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No.4,568,343); amides and other nitrogenous compounds such as urea,dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone® and sulfoxides such as DMSO andC₁₀MSO may also be used, but are less preferred. As noted earlierherein, Percutaneous Penetration Enhancers, eds. Smith et al. (CRCPress, 1995) provides an excellent overview of the field and furtherinformation concerning possible secondary enhancers for use inconjunction with the present invention.

The formulation may also contain irritation-mitigating additives tominimize or eliminate the possibility of skin irritation or skin damageresulting from the peptidyl drug, the enhancer, or other components ofthe formulation. Suitable irritation-mitigating additives include, forexample: α-tocopherol; monoamine oxidase inhibitors, particularly phenylalcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids andsalicylates; ascorbic acids and ascorbates; ionophores such as monensin;amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanicacid; capsaicin; and chloroquine. The irritant-mitigating additive, ifpresent, may be incorporated into the present formulations at aconcentration effective to mitigate irritation or skin damage, typicallyrepresenting not more than about 20 wt. %, more typically not more thanabout 5 wt. %, of the formulations.

The concentration of the active agent in the formulation can vary agreat deal, and will depend on a variety of factors, including thedisease or condition to be treated, the nature and activity of theactive agent, the desired effect, possible adverse reactions, theability and speed of the active agent to reach its intended target, andother factors within the particular knowledge of the patient andphysician. Preferred formulations will typically contain on the order ofabout 0.5 wt. % to 50 wt. %, optimally about 10 wt. % to 30 wt. %,active agent.

Drug Delivery Systems:

An alternative and preferred method involves the use of a drug deliverysystem, e.g., a topical or transdermal “patch,” wherein the active agentis contained within a laminated structure that is to be affixed to theskin. In such a structure, the drug composition is contained in a layer,or “reservoir,” underlying an upper backing layer. The laminatedstructure may contain a single reservoir, or it may contain multiplereservoirs.

In one embodiment, the reservoir comprises a polymeric matrix of apharmaceutically acceptable adhesive material that serves to affix thesystem to the skin during drug delivery; typically, the adhesivematerial is a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin contact, and which should be physically and chemicallycompatible with the active agent, hydroxide-releasing agent, and anycarriers, vehicles or other additives that are present. Examples ofsuitable adhesive materials include, but are not limited to, thefollowing: polyethylenes; polysiloxanes; polyisobutylenes;polyacrylates; polyacrylamides; polyurethanes; plasticizedethylene-vinyl acetate copolymers; and tacky rubbers such aspolyisobutene, polybutadiene, polystyrene-isoprene copolymers,polystyrene-butadiene copolymers, and neoprene(polychloroprene).Preferred adhesives are polyisobutylenes.

The backing layer functions as the primary structural element of thetransdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing drug, hydroxide-releasing agent orcomponents of the formulation contained within the device. The backingis preferably comprised of a flexible elastomeric material that servesas a protective covering to prevent loss of drug and/or vehicle viatransmission through the upper surface of the patch, and will preferablyimpart a degree of occlusivity to the system, such that the area of thebody surface covered by the patch becomes hydrated during use. Thematerial used for the backing layer should permit the device to followthe contours of the skin and be worn comfortably on areas of skin suchas at joints or other points of flexure, that are normally subjected tomechanical strain with little or no likelihood of the device disengagingfrom the skin due to differences in the flexibility or resiliency of theskin and the device. The materials used as the backing layer are eitherocclusive or permeable, as noted above, although occlusive backings arepreferred, and are generally derived from synthetic polymers (e.g.,polyester, polyethylene, polypropylene, polyurethane, polyvinylidinechloride and polyether amide), natural polymers (e.g., cellulosicmaterials) or macroporous woven and nonwoven materials.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice so that the system may be affixed to the skin. The release linershould be made from a drug/vehicle impermeable material, and is adisposable element which serves only to protect the device prior toapplication. Typically, the release liner is formed from a materialimpermeable to the pharmacologically active agent and thehydroxide-releasing agent, and which is easily stripped from thetransdermal patch prior to use.

In an alternative embodiment, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir. In such a case, the reservoir may bea polymeric matrix as described above. Alternatively, the reservoir maybe comprised of a liquid or semisolid formulation contained in a closedcompartment or “pouch,” or it may be a hydrogel reservoir, or may takesome other form. Hydrogel reservoirs are particularly preferred herein.As will be appreciated by those skilled in the art, hydrogels aremacromolecular networks that absorb water and thus swell but do notdissolve in water. That is, hydrogels contain hydrophilic functionalgroups that provide for water absorption, but the hydrogels arecomprised of crosslinked polymers that give rise to aqueousinsolubility. Generally, then, hydrogels are comprised of crosslinkedhydrophilic polymers such as a polyurethane, a polyvinyl alcohol, apolyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone, apoly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixturethereof. Particularly preferred hydrophilic polymers are copolymers ofHEMA and polyvinylpyrrolidone.

Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe a drug, a hydroxide-releasing agent, an additional enhancer, or someother component contained in the drug delivery system.

A rate-controlling membrane, if present, will be included in the systemon the skin side of one or more of the drug reservoirs. The materialsused to form such a membrane are selected to limit the flux of one ormore components contained in the drug formulation. Representativematerials useful for forming rate-controlling membranes includepolyolefins such as polyethylene and polypropylene, polyamides,polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetatecopolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinylethylacetate copolymer, ethylene-vinyl propylacetate copolymer,polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and thelike.

Generally, the underlying surface of the transdermal device, i.e., theskin contact area, has an area in the range of about 5 cm² to 200 cm²,preferably 5 cm² to 100 cm², more preferably 20 cm² to 60 cm². That areawill vary, of course, with the amount of drug to be delivered and theflux of the drug through the body surface. Larger patches will benecessary to accommodate larger quantities of drug, while smallerpatches can be used for smaller quantities of drug and/or drugs thatexhibit a relatively high permeation rate.

Such drug delivery systems may be fabricated using conventional coatingand laminating techniques known in the art. For example, adhesive matrixsystems can be prepared by casting a fluid admixture of adhesive, thepeptidyl drug and vehicle onto the backing layer, followed by laminationof the release liner. Similarly, the adhesive mixture may be cast ontothe release liner, followed by lamination of the backing layer.Alternatively, the drug reservoir may be prepared in the absence of drugor excipient, and then loaded by “soaking” in a drug/vehicle mixture. Ingeneral, transdermal systems of the invention are fabricated by solventevaporation, film casting, melt extrusion, thin film lamination, diecutting, or the like. The hydroxide-releasing agent will generally beincorporated into the device during patch manufacture rather thansubsequent to preparation of the device.

In a preferred delivery system, an adhesive overlayer that also servesas a backing for the delivery system is used to better secure the patchto the body surface. This overlayer is sized such that it extends beyondthe drug reservoir so that adhesive on the overlayer comes into contactwith the body surface. The overlayer is useful because the adhesive/drugreservoir layer may lose its adhesion a few hours after application dueto hydration. By incorporating such an adhesive overlayer, the deliverysystem remains in place for the required period of time.

Other types and configurations of transdermal drug delivery systems mayalso be used in conjunction with the method of the present invention,i.e., the use of a hydroxide-releasing agent as a permeation enhancer,as will be appreciated by those skilled in the art of transdermal drugdelivery. See, for example, Ghosh, Transdermal and Topical Drug DeliverySystems (Interpharm Press, 1997), particularly Chapters 2 and 8.

As with the topically applied formulations of the invention, thecomposition containing drug and hydroxide-releasing agent within thedrug reservoir(s) of these laminated system may contain a number ofcomponents. In some cases, the drug and hydroxide-releasing agent may bedelivered “neat,” i.e., in the absence of additional liquid. In mostcases, however, the drug will be dissolved, dispersed or suspended in asuitable pharmaceutically acceptable vehicle, typically a solvent orgel. Other components which may be present include preservatives,stabilizers, surfactants, and the like.

Utility:

Peptidyl drugs are powerful agents used to treat a variety of conditionsor diseases. The clinical use of peptidyl drugs includes, for example,replacement or augmentation of a naturally occurring protein in anindividual suffering from a lack of that particular protein. Peptidyldrugs may also possess antagonistic activity, so as to reduce, forexample, the action of a naturally occurring peptide or protein causingan undesirable physiological effect. In addition, peptidyl drugs such asthe peptidyl endorphins may be employed as agents to alleviate pain.

The amount of drug administered and present in the formulations and drugdelivery systems of the invention is an amount required to achieve aneffective therapeutic result. Such an amount depends on many factors,such as the minimum necessary dosage of the drug for the particularindication being treated; the solubility and permeability of the carrierand adhesive layer in a drug delivery system, if one is used, and theperiod of time for which the hydroxide releasing-agent and/or devicewill be affixed to the skin or other body surface. The minimum amount ofdrug is determined by the requirement that a sufficient quantity of drugmust be present in the device to maintain the desired rate of releaseover the given period of application. The maximum amount for safetypurposes is determined by the requirement that the quantity of drugpresent cannot exceed a rate of release that reaches toxic levels.Generally, the maximum concentration is determined by the amount ofagent that can be received in the carrier without producing adversehistological effects such as irritation, an unacceptably high initialpulse of agent into the body, or adverse effects on the characteristicsof the delivery device such as the loss of tackiness, viscosity, ordeterioration of other properties.

In treating an individual with a peptidyl drug-responsive condition ordisease, the peptidyl drug is administered to a localized region ofindividual's body surface in combination with a hydroxide-releasingagent. The peptidyl drug and hydroxide-releasing agent are applied tothe body surface in a predetermined amount effective to enhance the fluxof the peptidyl drug through the predetermined area of the body surfacewithout causing damage thereto.

The invention accordingly provides a novel and highly effective meansfor increasing the flux of a peptidyl agent through the body surface(skin or mucosal tissue) of a human or animal. The hydroxide-releasingagents discussed herein, employed in specific amounts relative to asolution, formulation or drug reservoir, may be used as permeationenhancers with a variety of peptidyl drugs. Surprisingly, the increasein permeation is not accompanied by any noticeable tissue damage,irritation, or sensitization. The invention thus represents an importantadvance in the field of drug delivery.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description, as well as the examples which follow, areintended to illustrate and not limit the scope of the invention. Otheraspects, advantages and modifications will be apparent to those skilledin the art to which the invention pertains. All patents, patentapplications, journal articles and other references cited herein areincorporated by reference in their entireties.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the materials of the invention, and are not intended tolimit the scope of what the inventors regard as their invention. Effortshave been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. and pressure is at or near atmospheric.

EXAMPLE 1

An in vitro skin permeation study was conducted using three leuprolidesolutions. The formulations used to prepare these systems are listed inTable 1, which include weight and weight percent of each ingredient inthe formulations. The weight of sodium hydroxide was 0 g, 0.0125 g, and0.0275 g for formulation #Leu-S1, #Leu-S2 and #Leu-S3, respectively.Each formulation was stirred until the solution was uniform.

The in-vitro permeation of each leuprolide solution through humancadaver skin was performed using Franz-type diffusion cells with adiffusion area of 1 cm². The volume of receiver solution was 8 ml. Humancadaver skin was cut to a proper size and placed on a flat surface withthe stratum corneum side facing up. The skin was clamped between thedonor and receiver chambers of the diffusion cell, and the stratumcorneum was allowed to dry. The leuprolide solution was applied to thestratum corneum using a micro-pipette. Each formulation was applied in a25 μl dosage and a 50 μl dosage for a total of 6 test groups. Thereceiver chamber was sealed to the atmosphere using parafilm wrap sothat it was spill-proof and airtight. Three diffusion cells were usedfor each test group for a total of 18 cells.

The cells were filled with deionized (DI) water for a receiver solution.The DI water had been degased to remove air bubbles. The receiversolution was completely withdrawn and replaced with fresh DI water ateach time point. Samples of the receiver solution were taken andanalyzed by HPLC (high pressure liquid chromatography) to determine theleuprolide concentration. The cumulative amount of leuprolide acrosshuman cadaver skin (Table 2) was calculated using the measuredleuprolide concentrations in the receiver solutions for each time point.

TABLE 1 Weight and Weight Percent of Components (Based on Total SolutionWeight) for Three Leuprolide Transdermal Systems Leu-S1 Leu-S2* Leu-S3*Leuprolide 0.003 g (0.4%) 6.4 × 6.4 g × 10⁻⁴ g (0.18%) 10⁻⁴ g (0.16%) DIwater 0.45 g (64.0%) 0.28 g (80.9%) 0.33 g (80.3%) NaOH 0 g (0.0%)0.0125 g (3.6%) 0.0275 g (6.7%) Propylene 0.25 g (35.6%) 0.053 g (15.3%)0.053 g (13.0%) Glycol *Solutions Leu-s2 and Leu-3 were prepared using0.15 g of Leu-S1, then adding the correct amount of NaOH and DI water.Percentages may not add up to 100% due to rounding.

TABLE 2 Cumulative Amount of Leuprolide Permeated Across Human CadaverSkin From a 25 μl and a 50 μl Solution Containing NaOH at 5-hour and24-hour Time Points (μg/cm²) Leu-S1 Leu-S2 Leu-S3 Leu-S1 Leu-S2 Leu-S325 μl 25 μl 25 μl 50 μl 50 μl 50 μl  5 hours 0.38 0.52 0.58 0.32 0.620.3 24 hours 0.52 3.21 4.43 0.32 8.58 10.8

The cumulative amount of leuprolide across human cadaver skin for the 25μl dosage at 24 hours increased from 0.52 μg/cm² to 4.43 μg/cm² when thecalculated sodium hydroxide concentration in the dried patch wasincreased from 0% to 6.7%. The cumulative amount of leuprolide acrosshuman cadaver skin for the 50 μl dosage at 24 hours increased from 0.32μg/cm² to 10.8 μg/cm² when the calculated sodium hydroxide concentrationin the leuprolide solution was increased from 0% to 6.7%. The cumulativeamount of leuprolide across human cadaver skin at 24 hours from the 50μl dosage group containing 3.6% NaOH (Leu-S2) was 8.58 μg/cm², which wasabout 27 times higher than that from the formulation without NaOH (0.32μg/cm², #Leu-S1).

EXAMPLE 2

The in-vitro permeation of oxytocin through human cadaver skin wasperformed using Franz-type diffusion cells with a diffusion area of 1cm². The volume of receiver solution was 8 ml. Human cadaver skin wascut to a proper size and placed on a flat surface with the stratumcorneum side facing up. The skin was clamped between the donor andreceiver chambers of the diffusion cell. Eighteen diffusion cells wereused in this study. A 2% NaOH aqueous solution (50 μl) was introduced tothe donor chambers of nine cells (cells #1 to 9) and a 4% NaOH aqueoussolution (50 μl) was introduced to the donor chambers of the other ninecells (cells #10 to 18). Once the NaOH solution is applied, the donorchamber was covered with parafilm.

After 5 hours, the NaOH solution was washed away from the skin for 3cells (cells #1 to 3) that were treated with 2% NaOH solution and 3cells (cells #10 to 12) that were treated with 4% NaOH solution. After10 hours, the NaOH solution was washed away from the skin for 3 cells(cells #4 to 6) that were treated with 2% NaOH solution and 3 cells(cells #13 to 15) that were treated with 4% NaOH solution. After 24hours, the NaOH solution was washed away from the skin for 3 cells(cells #7 to 9) that were treated with 2% NaOH solution and 3 cells(cells #16 to 18) that were treated with 4% NaOH solution. To wash awaythe NaOH solution, the receiving fluid was removed and replaced withfresh DI water. This was done twice. DI water was added to the donorchamber to dilute the NaOH solution and then the donor solution wasremoved. This was repeated several times.

After the NaOH solution was washed away from the skin, the solution inthe donor chamber was completely removed and replaced by 50 μl of anoxytocin solution. The formulation of the oxytocin solution is listed inTable 3. Once the oxytocin solution is applied, the donor chamber wascovered with parafilm.

The cells were filled with DI water as a receiver solution. The DI waterhad been degased to remove air bubbles. The receiver solution wascompletely withdrawn and replaced with fresh DI water at each timepoint. The samples taken were analyzed by HPLC for the concentration ofoxytocin in the receiver solution. The cumulative amount of oxytocinacross human cadaver skin was calculated using the measured oxytocinconcentrations in the receiver solutions for each time point, which werelisted in Table 4.

TABLE 3 Formulation for the Oxytocin Solution Oxytocin 0.005 g DI water0.6 g Propylene Glycol 0.6 g

TABLE 4 Cumulative Amount of Oxytocin Permeated Across Human CadaverSkin From an Oxytocin Solution (μg/cm²) Skin pretreated Skin pretreatedSkin pretreated by 4% by 4% by 4% NaOH for 5 hr NaOH for 15 hr NaOH for24 hr  5 hours 118.95 202.28 193.82 15 hours 200.66 222.45 232.72 24hours 225.52 231.58 236.80

EXAMPLE 3

The in-vitro permeation of oxytocin through human cadaver skin wasperformed using Franz-type diffusion cells with a diffusion area of 1cm². The volume of receiver solution was 8 ml. Human cadaver skin wascut to a proper size and placed on a flat surface with the stratumcorneum side facing up. The skin was clamped between the donor andreceiver chambers of the diffusion cell. Eighteen diffusion cells wereused in this study. A 0.25% NaOH aqueous solution (50 μl) was introducedto the donor chambers of nine cells (cells #1 to 9) and A 1.0% NaOHaqueous solution (50 μl) was introduced to the donor chambers of theother nine cells (cells #10 to 18). Once the NaOH solution is applied,the donor chamber was covered with parafilm.

After 5 hours, the NaOH solution was washed away from the skin for 3cells (cells #1 to 3) that were treated with 0.5% NaOH solution and 3cells (cells #10 to 12) that were treated with 1.0% NaOH solution. After11 hours, the NaOH solution was washed away from the skin for 3 cells(cells #4 to 6) that were treated with 0.25% NaOH solution and 3 cells(cells #13 to 15) that were treated with 1.0% NaOH solution. After 24hours, the NaOH solution was washed away from the skin for 3 cells(cells #7 to 9) that were treated with 0.25% NaOH solution and 3 cells(cells #16 to 18) that were treated with 1.0% NaOH solution. To washaway the NaOH solution, the receiving fluid was removed and replacedwith fresh DI water. This was done twice. DI water was added to thedonor chamber to dilute the NaOH solution and then the donor solutionwas removed. This was repeated several times until the pH of donorsolution was less than 8.

After the NaOH solution was washed away from the skin, the solution inthe donor chamber was completely removed and replaced by 50 μl of anoxytocin solution. The formulation of the oxytocin solution is listed inTable 5. Once the oxytocin solution is applied, the donor chamber wascovered with parafilm.

The cells were filled with DI water as a receiver solution. The DI waterhas been degased to remove air bubbles. The receiver solution wascompletely withdrawn and replaced with fresh DI water at each timepoint. The samples taken were analyzed by an HPLC for the concentrationof oxytocin in the receiver solution. The cumulative amount of oxytocinacross human cadaver skin was calculated using the measured oxytocinconcentrations in the receiver solutions for each time point, which werelisted in Table 6.

TABLE 5 Formulation for the Oxytocin Solution Oxytocin 0.005 g DI water0.6 g Propylene Glycol 0.6 g

TABLE 6 Cumulative Amount of Oxytocin Permeated Across Human CadaverSkin From an Oxytocin Solution (μg/cm²) Skin pretreated Skin pretreatedSkin pretreated by 1.0% by 1.0% by 1.0% NaOH for 5 hr NaOH for 11 hrNaOH for 24 hr 4.25 hours 0.45 53.42 13.23 14.75 hours 0.97 67.97 21.0624 hours 0.97 75.36 30.97

We claim:
 1. A method for enhancing the flux of a peptidyl drug througha body surface, comprising administering the peptidyl drug to alocalized region of a human patient's body surface in combination with ahydroxide-releasing agent applied to the body surface in a predeterminedamount effective to enhance the flux of the drug through the localizedregion of the body surface without causing damage thereto, and effectiveto provide a pH in the range of approximately 8.5 to 11.5 at thelocalized region of the body surface, during drug administration,wherein the peptidyl drug and hydroxide-releasing agent are present in aformulation and the amount of hydroxide-releasing agent in theformulation applied to the body surface is the total of (a) the amountrequired to neutralize any acidic species in the formulation plus (b) anamount equal to approximately 0.25 wt. % to 25.0 wt. % of theformulation.
 2. The method of claim 1, wherein the body surface is skin.3. The method of claim 1, wherein the body surface is mucosal tissue. 4.The method of claim 1, wherein the formulation is aqueous.
 5. The methodof claim 4, wherein the formulation has a pH in the range ofapproximately 8.0 to
 13. 6. The method of claim 5, wherein the pH is inthe range of approximately 8.0 to 11.5.
 7. The method of claim 6,wherein the pH is in the range of approximately 8.5 to 11.5.
 8. Themethod of claim 4, wherein the aqueous formulation is selected from thegroup consisting of a cream, a gel, a lotion, and a paste.
 9. The methodof claim 8, wherein the formulation is a cream.
 10. The method of claim8, wherein the formulation is a gel.
 11. The method of claim 1, whereinthe formulation is nonaqueous.
 12. The method of claim 11, wherein theformulation is an ointment.
 13. The method of claim 1, wherein thehydroxide-releasing agent releases free hydroxide ions in the presenceof an aqueous fluid.
 14. The method of claim 1, wherein thehydroxide-releasing agent is selected from the group consisting ofinorganic hydroxides, inorganic oxides, metal salts of weak acids, andmixtures thereof.
 15. The method of claim 14, wherein thehydroxide-releasing agent is an inorganic hydroxide.
 16. The method ofclaim 15, wherein the inorganic hydroxide is selected from the groupconsisting of ammonium hydroxide, alkali metal hydroxides, alkalineearth metal hydroxides, and mixtures thereof.
 17. The method of claim16, wherein the inorganic hydroxide is selected from the groupconsisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide,potassium hydroxide, magnesium hydroxide, and mixtures thereof.
 18. Themethod of claim 17, wherein the inorganic hydroxide is sodium hydroxide.19. The method of claim 18, wherein the inorganic hydroxide is potassiumhydroxide.
 20. The method of claim 14, wherein the hydroxide-releasingagent is an inorganic oxide.
 21. The method of claim 20, wherein theinorganic oxide is selected from the group consisting of magnesiumoxide, calcium oxide and mixtures thereof.
 22. The method of claim 14,wherein the hydroxide-releasing agent is a metal salt of a weak acid.23. The method of claim 22, wherein the hydroxide-releasing agent isselected from the group consisting of sodium acetate, sodium borate,sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodiumphosphate, dibasic sodium phosphate, potassium carbonate, potassiumbicarbonate, potassium citrate, potassium acetate, dibasic potassiumphosphate, tribasic potassium phosphate, dibasic ammonium phosphate, andmixtures thereof.
 24. The method of claim 23, wherein the amount ofinorganic hydroxide in the formulation is the total of (a) the amountrequired to neutralize any acidic species in the formulation plus (b) anamount equal to approximately 0.25 wt. % to 7.0 wt. % of theformulation.
 25. The method of claim 24, wherein the amount of inorganichydroxide in the formulation is the total of (a) the amount required toneutralize any acidic species in the formulation plus (b) an amountequal to approximately 0.5 wt. % to 4.0 wt. % of the formulation. 26.The method of claim 25, wherein the amount of inorganic hydroxide in theformulation is the total of (a) the amount required to neutralize anyacidic species in the formulation plus (b) an amount equal toapproximately 0.75 wt. % to 2.0 wt. % of the formulation.
 27. The methodof claim 26, wherein the amount of inorganic hydroxide in theformulation is the total of (a) the amount required to neutralize anyacidic species in the formulation plus (b) an amount equal toapproximately 1.0 wt. % of the formulation.
 28. The method of claim 20,wherein the formulation contains up to approximately 25 wt. % of thehydroxide-releasing agent.
 29. The method of claim 28, wherein theformulation contains up to approximately 20 wt. % of thehydroxide-releasing agent.
 30. The method of claim 1, wherein thepeptidyl drug and hydroxide-releasing agent are administered by applyinga drug delivery device to the localized region of the patient's bodysurface thereby forming a body surface-delivery device interface, thedevice comprising the peptidyl drug and the hydroxide-releasing agent,and having an outer backing layer that serves as the outer surface ofthe device during use.
 31. The method of claim 30, wherein the peptidyldrug and hydroxide-releasing agent are present in an adhesive, gel orliquid formulation contained within the device.
 32. The method of claim30, wherein the outer backing layer is occlusive.
 33. The method ofclaim 1, wherein the peptidyl drug is administered in combination withan additional permeation enhancer.
 34. The method of claim 1, whereinthe peptidyl drug is systemically acting and administration istransdermal.
 35. The method of claim 1, wherein the peptidyl drug andhydroxide-releasing agent are administered without any additionalpermeation enhancer.
 36. The method of claim 1, wherein the peptidyldrug is a peptide.
 37. The method of claim 1, wherein the peptidyl drugis a polypeptide.
 38. The method of claim 1, wherein the peptidyl drugis a protein.
 39. The method of claim 1, wherein the peptidyl drug isselected from the group consisting of coagulation modulators, cytokines,endorphins, kinins, peptidyl hormones, LHRH analogs and combinationsthereof.
 40. The method of claim 39, wherein the peptidyl drug is acoagulation modulator.
 41. The method of claim 40, wherein the peptidyldrug is selected from the group consisting of α₁-antitrypsin,α₂-macroglobulin, antithrombin III, factor I, factor II, factor III,factor V, factor VII, factor VIII, factor IX, factor X, factor XI,factor XII, heparin cofactor II, kallikrein, plasmin, plasminogen,prekallikrein, protein C, protein S, thrombomodulin and combinationsthereof.
 42. The method of claim 39, wherein the peptidyl drug is acytokine.
 43. The method of claim 42, wherein the peptidyl drug isselected from the group consisting of colony stimulating factor 4,heparin binding neurotrophic factor, interferon-α, interferon α-2a,interferon α-2b, interferon α-n3, interferon-β, interferon-γ,interleukin-1, interleukin-2, interleukin-3, interleukin-4,interleukin-5, interleukin-6, interleukin-7, interleukin-8,interleukin-9, interleukin-10, interleukin-11, interleukin-12,interleukin-13, interleukin-14, interleukin-15, interleukin-16,interleukin-17, tumor necrosis factor, tumor necrosis factor-α,granuloycte colony-stimulating factor, granulocyte-macrophagecolony-stimulating factor, macrophage colony-stimulating factor,midkine, thymopoietin and combinations thereof.
 44. The method of claim39, wherein the peptidyl drug is an endorphin.
 45. The method of claim44, wherein the peptidyl drug is selected from the group consisting ofdermorphin, dynorphin, α-endorphin, β-endorphin, γ-endorphin,σ-endorphin [Leu⁵]enkephalin, [Met⁵]enkephalin, substance P, andcombinations thereof.
 46. The method of claim 39, wherein the peptidyldrug is a kinin.
 47. The method of claim 46, wherein the peptidyl drugis selected from the group consisting of bradykinin, potentiator B,bradykinin potentiator C, kallidin and combinations thereof.
 48. Themethod of claim 39, wherein the peptidyl drug is a peptidyl hormone. 49.The method of claim 48, wherein the peptidyl drug is selected from thegroup consisting of activin, amylin, angiotensin, atrial natriureticpeptide, calcitonin, calcitonin gene-related peptide, calcitoninN-terminal flanking peptide, cholecystokinin, ciliary neurotrophicfactor, corticotropin, corticotropin-releasing factor, epidermal growthfactor, follicle-stimulating hormone, gastrin, gastrin inhibitorypeptide, gastrin-releasing peptide, ghrelin, glucogon,gonadotropin-releasing factor, growth hormone releasing factor, humanchorionic gonadotropin, inhibin A, inhibin B, insulin, leptin,lipotropin, luteinizing hormone, luteinizing hormone-releasing hormone,α-melanocyte-stimulating hormone, β-melanocyte-stimulating hormone,γ-melanocyte-stimulating hormone, melatonin, motilin, oxytocin,pancreatic polypeptide, parathyroid hormone, placental lactogen,prolactin, prolactin-release inhibiting factor, prolactin-releasingfactor, secretin, somatotropin, somatostatin, thyrotropin,thyrotropin-releasing factor, thyroxine, triiodothyronine, vasoactiveintestinal peptide, vasopressin and combinations thereof.
 50. The methodof claim 49, wherein the peptidyl drug is oxytocin.
 51. The method ofclaim 39, wherein the peptidyl drug is an LHRH analog.
 52. The method ofclaim 51, wherein the peptidyl drug is selected from the groupconsisting of buserelin, deslorelin, fertirelin, goserelin, histrelin,leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof.53. The method of claim 52, wherein the peptidyl drug is leuprolide. 54.The method of claim 1, wherein the peptidyl drug is selected from thegroup consisting of abarelix, adenosine deaminase, anakinra, ancestim,alteplase, alglucerase, asparaginase, bivalirudin, bleomycin, bombesin,desmopressin acetate, des-Q14-ghrelin, dornase-α, enterostatin,erythropoeitin, exendin-4, fibroblast growth factor-2, filgrastim,β-glucocerebrosidase, gonadorelin, hyaluronidase, insulinotropin,lepirudin, magainin I, magainin II, nerve growth factor, pentigetide,thrombopoietin, thymosin α-1, thymidin kinase, tissue plasminogenactivator, tryptophan hydroxylase, urokinase, urotensin II andcombinations thereof.